We propose to study two classes of naturally occurring antineoplastic agents - the quassinoids and the sesquiterpene lactones. Both are potent inhibitors of protein synthesis in eukaryotic cells. With both the quassinoid antineoplastics and the sesquiterpene lactones we plan to concentrate first on elucidating their detailed mechanism of action. In particular we plan to study 1) their uptake by the cell 2) whether they bind reversibly or irreversibly to the cell, and 3) exactly how they inhibit protein synthesis. With the quassinoid antineoplastics we plan to examine several other questions as well. In the first place, we plan to look at their effectiveness against various neoplastic cell lines and compare their in vitro effect as protein synthesis inhibitors with their in vivo effect against the corresponding tumors in the whole animal. Secondly, we plan to look at the selectivity of different analogs as protein synthesis inhibitors for neoplastic versus normal tissue and compare in vivo. Finally, we plan to look at the interaction of these different analogs with the peptidyl transferase center of the ribosomes derived from different tissue. Hopefully, we will find that some of these compounds can be used as probes to distinguish small structural differences between the ribosomes of various tissues.